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GWAS Linking Prostate Cancer to Androgen Receptor Binding Site related SNPs
Overview ] Recently, incidence of prostate cancer has been linked to certain SNPs found in the binding sites of the androgen receptor. The androgen receptor is a nuclear receptor for steroid hormones called androgens that are typically involved in male development. Once these hormones bind to the receptor, they can dimerize and act as a transcription factor in the activation of a gene's expression. The most well known androgen hormone that binds this receptor is testosterone, a critical hormone for development. Dysfunction in this receptor and its binding site can cause a wide variety of defects, both developmental and pathological, which are typically due to mutations in the receptor itself or the DNA site to which it binds. Its relation to prostate cancer is understood to be due to the fact that the androgen receptor's normal function is to regulate prostate growth, but can undergo alternate signal pathways that have the ability to increase prostate cancer cell proliferation.Lonergan, P., Tindall, D. (2001). Androgen receptor signaling in prostate cancer development and progression. J Carcinog. 10: 20. [http://www.ncbi.nlm.nih.gov.ezproxy.uvm.edu/pubmed/21886458 PubMed] GWAS Study and Findings Prior to this study, there were 33 SNPs identified as risk factors for prostate cancer that other groups had iidentified with an enhanced incidence in androgen receptor binding sites. To test that SNPs in the binding region of the androgen receptor lead to prostate cancer risk, a population of 1, 964 individuals with treated prostate cancer and 3, 172 without prostate cancer were subjected to GWAS. There was also a second study conducted in a similar manner. To perform the studies, ChIP assays were performed for the known androgen receptor binding sites, a total of 22,447 sequences, to find SNP occurrence and frequency within the studied subjects. In addition, the 33 risk SNPs that were previously idenditfied were studied for association with other SNPS through established linkage disequilibrium blocks and incidence of cancer risk. Of the 22,447 SNP sequences for androgen receptor binding sites, 12,724 were assessed for prostate cancer risk in which 4 linkage disequilibrium blocks were identified to contain a SNP that is strongly related to prostate cancer in the first study and 2 in the second study. These blocks were found to be at 8p21 (study 1), 10q11 (Study 1), and two at 8q24 (studies 1 and 2), and 15q21 (study 2). In relation to previously known prostate cancer SNPs in previous studies, it was found that many overlapped with blocks containing the SNPs identified. It was also found that as data became more statistically significant in terms of association, percentage chance of overlap increased. Findings of this study were twofold in that it linked both regions of androgen receptor binding to SNPs with elevated prostate cancer risk as well as identifying their relation of previously described SNPs in the androgen receptor binding region with an elevated rink in comparison to other regions. In terms of molecular significance, one of the discovered SNP containing regions (8p21) was found to be in the region containing the NKX3.1 gene. This is important in terms of prostate cancer because it encodes for prostate differentiation and tumor suppression transcription factor. The most commonly associated region (8p24) was identified for the first time in this study to be an androgen receptor regulation site. SNPs in this region can have a variety of consequences, most notably encoding for a prostate enhancer that has been directly linked to cancer in a manner similar to the Myc gene and transcription factor. This is important because Myc function is important in cell cycle regulation as well as apoptosis, dysfunctions of which lead to cancerMyc myelocytomatosis oncogene, NCBI gene database. 29 Oct, 2014 [http://www.ncbi.nlm.nih.gov/gene/17869 Link], and mimicking this function could be an alternate path to prostate cancer. The authors indicate a level of caution in regards to their findings, noting that results could be due to false positives given by cutoffs for statistical significance, that the study only looks at statistics, and that experimental evidence needs to be collected to determine the true nature of the binding sites observed. Lu, Y et al. (2012) Association of prostate cancer risk with SNPs in regions containing androgen receptor binding sites captured by ChIP-on-chip analyses. Prostate. 72(4):376-85 [http://www.ncbi.nlm.nih.gov/pubmed/21671247 PubMed] References